Shigellae are Gram-negative bacteria, pathogens to humans only, that can cause endemic and epidemic dysentery worldwide, especially in the developing countries. It has been estimated that ≈160 million cases of shigellosis with ≈1 million deaths occurring worldwide annually. At least half of the cases and deaths are believed to occur in children <5 years old. Control of this disease is hampered by the low infectious dose of this pathogen (<100 bacteria) and lack of safe drinking water and food in the developing world. The symptoms usually start with watery diarrhea that later develops into dysentery, characterized by high fever, blood and mucus in the stool, and cramps.
Lipopolysaccharides (LPSs) of Shigella are both essential virulence factors and protective antigens of this genus. The outer domain of this tripartite molecule, termed O-specific polysaccharide (O-SP), “shields” the bacteria from serum complement killing, similar to the action of capsular polysaccharides. It has been hypothesized that serum antibodies to the O-SP of shigellae confer immunity to humans against the homologous bacteria. To test this hypothesis, experimental vaccines composed of protein conjugates of the O-SP of Shigella dysenteriae type 1, Shigella sonnei, and Shigella flexneri 2a were synthesized and evaluated in young adults. Evaluation of a S. sonnei O-SP/recombinant Pseudomonas aeruginosa Exotoxin A (rEPA) conjugate in Israeli soldiers demonstrated 72% efficacy with vaccine failures occurring in individuals who responded with significantly lower serum antibody levels than those who were protected. Evaluation of such conjugates in children showed age-related antibody responses and protection. A significant improvement in the immunogenicity of S. dysenteriae type 1 conjugates was achieved by using synthetic oligosaccharides (OS) of defined lengths bound by their reducing ends to a protein at defined densities. Unfortunately, this improvement could not be replicated for S. sonnei, as synthesis of S. sonnei O-SP oligosaccharides has not been possible to date. Thus, the need still exists for improved S. sonnei specific vaccines. The conjugates and methods of treatment disclosed herein meet those needs.